Staging- Where Is It
FINDING JUS ONE CANCER CELL SENS AND SPECIFICITY NOW
BEYOND SIMGLE CELL DETECTION
Treatment Modalities, Goals and Timing
Potions and Poisons -Chemotherapy and Other Potions MORE IN DEPTH
What is The Buzz-Radiation Therapy
A Chance to Cut – A Chance to Cure-Principles of Surgical Oncology
MONOCLONAL ANTIBODIES AND OTHER BIOLOGIC THERAPIES
BONE MARRO TRANSPLANTS
PHOTODYNAMIC THERAPY AND LASER SO MUCH MORE VARIATIONS ON A THEME
Example of Finding Just One Cancer Cell
What follows in this section is a much more advanced presentation of the major ways we treat patients such as radiation, chemotherapy and surgery as well as some of the newer therapies. There is sufficient depth here for one who wishes to have a broad overview of one way to embrace the basic science principles (about late high school level per se). There is also sufficient depth layered in that is more like a Discovery Channel or Nova overview of how all the material connects. Again, I encourage you to look it over and certainly use it as a reference to better understand your options and more so the world of those professionals who are treating you.
You will be both amazed and awe struck at how we are wondrously assembled and how incredibly ingenious cancer cells disassemble the norm to their survival advantage. The sheer genius of the design and the methodical cleverness of the treatments being developed by talented men and woman worldwide as they unravel the nature of the cancer may deeply move you. Thus, there is something here for the student of science as well as a wow factor for all as we look at these therapies and their rationale.
They are also included because it is patients such as yourself not only supporting this work through your taxes but by enrolling in clinical trials ( to be discussed later) that have brought us this far. Thank you, and I hope this walk through these wonders helps calm the anxiety and embolden your power to fight right along with your health care team and when appropriate, to cheer on that this new age of enlightened endeavors make the weapons in the oncologist’s armamentarium grow.
Let us first look at the rationale and principles of treating starting from the not so hypothetical situation of having tests that find only one or only a few cancer cells in the blood. Large tumors within the level of detection (0.5 cm) are self-apparent; something must be done. However, there is a lot to be learned by looking at where technology is taking us in terms of early detection. There is a lot to be learned in terms of when to treat and why. So with that in mind, let us spend a little time examining lessons learned from the perspective of finding one or barely any malignant cells – what do we do and what do we think . How did it these cancer cells escape our own immune system, or did they?
Research at the cellular level looks for why does one cell and its progeny survive, escape surveillance and destruction by our immune system and grow beyond the limits of the normal counterpart cell that they mimic to some degree. Why do they spread, frequently homing in on specific normal tissues, displacing and destroying them? How do they do it? We do not have all the whys but the quality of questions is growing with each high quality answer.
No one wants to treat everyone who is found to have random malignant cells found accidentally or by intentional search just because they are there. No one wishes to ignore these cells all the time either. The same thinking applies to when you think you have a complete remission. How do you know what is enough therapy. How do you know you have a durable remission or cure. Often we do not know, but our tests are growing in leaps and bounds in terms of cell specific or cancer specific signs, symptoms and clues that cue us in that there is disease remaining. Our trials are telling us when and what therapies work best alone or together and when it is time to either stop or offer highly experimental treatment since all conventional therapy has failed.
At the millennium, The National Cancer Institute established a goal of eliminating the suffering and death due to cancer by 2015. This was noble but unrealistic. Much research is aimed at finding both the primary tumor as well as any metastases (sites of tumor spread) at the earliest ( fewest cells) time. Exactly when, where, how and why a distant metastasis of a primary tumor occurs is not clear in many cancers. In addition, it most certainly varies within patients with the same type of cancer as well as among cancers. For solid tumors we have a lot of data collected, using both cellular based techniques and imaging of tumor lesions of over 0.5 cm ( our present most common detection threshold) that gives us general ideas of the personality of both treated and non treated cancers in terms of the where and when of spreading.
Some cancers spread by direct invasion and may invade and spill over into lymphatic and vascular channels. Some not only seek out and seed into the blood, but actually home to predestined organs manipulating our own machinery and building cell sized canals to travel within as well as feed themselves by bringing them close to these new vessels.
A great deal of research has gone into detection beyond the level of the physical exam and human eye. We will delve a bit more deeply into this notion of applying critical thinking to observations made over the decades derived by pondering the exciting notion of trying to find just one cancer cell among billions.
Even if there is just one tumor cell found, is it clonagenic? This means can it and will it anchor in some organ, have just the right conditions for growth and have offspring. Will it survive long enough to have offspring before its own internal clock signals time to die? Will all the essential nutrient requirements be present? Can it evade assault by antibody and non antibody producing cells of your immune system before whatever clock internally it is under or whatever assault it is battered by ( immune system, oxygen content, acid base environment, and such do it in. Is finding it once in the circulating blood a marker that many malignant cells are circulating undetected.
Is finding it once a sufficient marker of high probability that among the other tumor cells that are facing the same challenges, at least one will succeed? Is there high certainty that blood involvement on this test seen once; is a marker for high likelihood of bone marrow involvement or brain as is the case with other cancers? Do cells in the blood constitute real and sufficient markers for patients to do poorly in some predictable way as is known for some solid (excluding primary hematologic) malignancies? When would we want to listen to the presence of one such cell in the blood?
Put another way, is the finding of one test, or whatever number you have showing cells of the tumor in the blood, of clinical relevance? If so what is it relevant to; total tumor burden, response rate, disease progression, overall survival and so on. Or as the title of the book implies, is this ( the positive circulating blood results) a rumor that does not imply serious consequences and underlying meanings as listed above or in fact is it the bell weather test that is saying where you see few, trust there are many?
In general, finding circulating leukemic cells in patients with acute leukemia must be taken in the context of where in the therapy you are. In chronic leukemia, the same concept is true, as, by definition, even stable disease and low-level disease will show the malignant cells. However, when so-called solid tumors cells are showing up in ever increasingly sophisticated assays of the blood, all the above big clinical questions arise.
Yes, the test is very important if a positive circulating malignant cell test means that where there is few there is many, ( such as a positive bone marrow with malignant cells in it) The standard reasoning ( if the realistic intent is cure and not palliation) is to treat the patient full dose on time initially with chemotherapy. Patients may not handle this as well and if you under treat the malignant cells will overgrow and resist the less than optimal dosing because of the probable marrow involvement. If you do not cleanse the marrow, the marrow may never recover and you may end up with the horrific possibility of a packed bone marrow with increasingly resistant cancer cells from insufficient dose. You will also have dependency on blood products. All of this transpired because we believed finding one positive circulating cell in solid tumors means the bone marrow is involved and that warrants, if treating for cure, full dose on time therapy.
As our technology grows we need to understand what the implications of their sensitivities are. It is not yet standard of care in clinical staging of solid tumors to assess patients’ blood or bone marrow to see if there are any circulating cells from the original cancer present which are actively circulating. Similarly, if the test is done, I am not clear as to what to do with a negative result.
If the test is negative and the patient has widespread disease, I feel you have added nothing. If it is negative with otherwise limited early stage disease I would be hesitant to treat an otherwise low stage patient with therapy meant for high stage without either new data showing the original staging was wrong or published research telling us how specific and sensitive the test is for predicting it behaving like advanced disease. The point is to be careful of what tests you do if careful review of published experience shows you that it is not clear what one does with the answer.
Might it make a difference if we could find cells circulating in the blood that presumably might be markers for cells trying to set up shop in distant lands? Intuitively, yes but again unless you have the data or are collecting it in an organized manner with patient consent to use it to get information that helps tailor your treatment, I would stay away from asking question whose answer you do not know how to address. I do support aggressively finding out through trials
This is why a number of companies have embarked to see if they can find circulating solid tumor cells in the blood. In the case of colon, prostate breast and lung (and in the literature, many tumors) the answer is yes. However, it is not clear if such detection is meaningful in the setting of a complete remission elsewhere or in the setting of a partial response. What do you with that?
In the case of leukemia, a large portion of what you do is aimed to have eradication of all leukemic clones (cancer cells capable of dividing) using all the tests there are to find them. These include looking for cell specific staining techniques to finding very specific molecules in or around or through their cell surface marking them uniquely from their benign counterparts. It continues to be our hope that earlier detection, even detection at the single circulating malignant cell in the bloodstream, might confer a different prognosis that might then argue for various therapies and combinations of treatments. In leukemia the argument holds true as by definition the tumor is of the bone marrow and diagnoses depends upon specific bone marrow findings primarily.
However, for the so-called solid tumors, we just do not know what finding circulating cells really means. One promising technique employs monoclonal antibodies that are discussed later but in brief are manmade antibodies engineered to be specific for something on, in or associated intimately with the cancer cell. You can put a marker or florescent tag or isotope on the antibody and look for the light (radiation) these tags emit. Then one can count the cells in a fluorescent activated cell sorter channel through which the blood flows learning how many cells were stained showing the presence of the marker. Of course, this requires both high specificity and sensitivity of the marker for the tumor cell associated antigen and strong binding affinity so that the monoclonal antibody does not easily fall off. Another recent style of detection is to have the antibodies have iron in them that then allows for an antibody iron bound complex if the antigen is present. Then when the cells are run through a sorter under a magnetic field, only the cells with the marker will stay on the magnet
So, all of this is to tell you that one should understand the natural history of the disease to which you are going to apply a test. Based on other results is it in the realm of possibility that cancer cells could be in the blood, what is the pre test probability? If it is profoundly low, you could be asking for confusion and having a result you have no use for except perhaps as research data. You would also want to know from prior controlled applications of the test in multiple scenarios and locations how sensitive (low false positive) and how specific (low false negative rate) the test was was when tested against known positive and negative controls, In other words how well is its yes correct and its no (tumor cells in blood) correct.
There may be a role for assays looking for single circulating cells in both seeming complete responders and major responders initially in collecting the data on all manners of patients to learn what the test can do, and in some cases directing further therapy as early as possible. The more we use the tool to collect that information, the more they can teach us.
It is not yet clear in which cancers ( other than most leukemias) this single cell detection really indentifies cells destined to survive in a new area and multiply. You cannot biopsy everywhere as you will usually be taking a sample.
Before you choose to take the test be sure you know how specific and sensitive a test is before using it and know whether there are any likely scenarios where the test results clearly changes prognosis.
Beyond Single Cell Detection
Our present conventional level of detection of internally seeing gross tumor is about 0.5 cm whether we use a CXR or Computed Axial Tomography (CAT scans are specialized X rays with computer assistance that bread-loafs slices images to 0.5 cm detail). Magnetic Resonance Imaging (MRI) (translates the movement of water under a massive magnetic force into images of incredible detail and again about 0.5 cm resolution.) These are frequently used to supplemental simple X rays, Ultrasound and various so-called nuclear medicine scans such as bone scan and PET scans. Ultrasound is good at looking at flow of fluids as well as densities and cavities and bone scan measures new bone being laid down in response to processes which ate away or destroyed prior bone such as fracture and repair, arthritis and in some classic patterns by tumor either of the bone or which has spread to bone. PET scans elegantly track the metabolism of isotopes of simple sugars in the brain and can be useful in the evaluation of both primary brain cancers and tumor that have spread to the brain which then take up the simple sugar you gave it thinking it nourishment of a sort.
After initial responses to treatment, one will have a very difficult time knowing if therapy had a positive sustainable benefit if you cannot easily see the tumor(s) using the above tests. You also do not know how viable any residual disease is, whether you see it or not. A spot on film might now be residual scar.
Ascertaining function of the cancer cells as mimicking normal counterparts will not be easy as only a few malignancies readily do that such as some thyroid cancers. Our tools of detection are imperfect with limits stated above. There can be problems with sensitivity of our studies when size is small which means that there is a high false negative rate wherein the test says the cancer cells are not there but in fact, they are and are out of our range of detection. Assays can also have a problem of not being sufficiently specific and have a high rate of false positives wherein the test incorrectly claims benign tissue to be cancerous.
Thus, an enormous of amount of research is looking into minimal residual disease and tests done of various biopsy type specimens or body regions that try to inform the clinician as to whether cells are present with the ability to divide and have ‘children’. This is not an exact science. There are so many other factors occurring at the same time we are making these measurements; the clinical condition of the patient, prior therapies, the condition of the bone marrow and other organs abilities to tolerate further therapy, the order of therapy and so on. Thus the research which looks for detecting disease at its lowest level of tumor burden tries to understand how that translates into the risk of a local, regional or systemically advanced disease.
With acute leukemia, the message is already clearly; kill every cell visible using all means of detection as just one cell could be clonal and lead to relapse. In solid tumors, this is not clear. No one wants to treat everyone who is found to have random malignant cells found after intentional search or just because they are there and no one wishes to ignore them out of hand. We must understand these delicate relationships before we miss an opportunity to improve therapy or choose wisely to stop when there is no proven disadvantage.
Breast cancer is a great example of how numerous factors mix in increasingly accurate mathematical prediction models to sort patients into risk groups and to define what groups will do best with which therapies. The hunt is on to add to the already considerable lists of factors we search for in every breast cancer patients and their cells. All of that informs us as to the risks and benefits of future therapy. This is poignantly true even though we do not see residual disease that in many is clearly there but not yet reliably detectable in most patients by any one particular assay.
Resolving benign Vs malignant is, in the case of breast cancer, the realm of the pathologist looking at tissue. There is usually no need for anything further to ascertain if breast biopsy cells are malignant. However, their personality and their likely future behavior can be ascertained with incredible detail and power by studying those specimens hormonally, genetically, biochemically, antigenically and immunologically. Some of these tests show either positive or negative, others give actual numbers of cells. Thus, we look for interior or surface of cell chemical binding sites which when present predict behavior. One may be able to use various immunologic trackers (antibodies that bind to a very specific portion of molecules known as antigens that are substances capable of eliciting an immune response, such as but not only antibody production). With these techniques, one can find individual cells among millions. Similarly, secondary chemical reactions can be triggered by the presence and interaction of a target seen only on malignant cells. Likewise, measurement and location of radiation given off when radio-immunocongjugates ( created by adding minuscule radiation to the binding antibody) prove the detection of a target protein seen in either only malignant cells or the more angry and apt to spread cells.
Sometimes we find receptors for common substances present or absent in the cancer cells, such as the receptor (think biochemical mailbox) for estrogen and progesterone. In the case of breast cancer, their presence is better than their absence and their presence opens up a whole class of drugs that can powerfully suppress the spread and growth of the clones (daughter cells) of cells that have the markers. Early work is suggesting putting various toxins or powerful radioisotopes that can tag some breast cancer cells on the antibody and deliver a toxic payload lethal to nearby cancer cells as well as those directly taking up or linking with this “ magic bullet “ antibody or antibody missile combination. Furthermore, you may see the breast cancer cells by looking for the radioactive light emitted by the injected isotope on targeted cancer cells.
I was fortunate to be on the first team to image breast cancer with a radiation labeled isotope monoclonal antibody showing not only where the bulk of tumor was but also finding previously undetected areas of spread by looking for the radioactive light. In addition, our team had humanized the antibody. Previously, a major obstacle was that the antibodies were largely from mouse origin and the human patient could react against them confounding their utility. This was a crucial first step to showing one could make and successfully use human antibodies (most previously were mouse), as human patients would reject mouse antibodies more often than not.
Thyroid cancer shows similar possibilities for diagnosis that also looks for protein production of the cells as well as uptake of building blocks for the protein as well. The cancer is an easy target for diagnostic uptake of radioisotopes At higher dose, therapeutic radiotherapy can target the tumor which absorbs it and thus receives a lethal dose to the cancer cells.
Thus, we are trying to exploit the fingerprint of the cell surface, or trans -membrane or cell body or nucleus or nucleus associated proteins, or genes and their products; anything the cancer cell possesses uniquely, or slightly aberrantly or in excess amount to its benign counterpart. This type of targeted therapy is a type of rational drug design; we sleuthed for vulnerabilities using the intricacies of the cancer cell as opposed to its benign counterpart and built near targeted bullets for only our intended prey.
Diagnostically, the more we understand any of the physical, genetic, molecular or immunologic and antigenic unique fingerprints of cancer cells, the more we can develop tests that exploit those differences. We can then “find”, with perhaps tagged on chemical or radioactive dyes, depots of malignant cells at much higher resolution than other techniques.
Therapeutically, finding the cells when they are less in number not only means less tumor burden, but probably better penetration into tumor depots and higher ratios of killed cells to viable cells. The tempo of such targeted therapy and rational drug design submissions to the FDA continues to pick up as the possibilities rumor of some animal or plant kingdom wonder drug. Similarly, the pace of thoughtful laboratory rational drug design based on finding more Achilles heels that tumor cells have as opposed to their normal counterparts which leads to rationally built drugs is accelerating. The numbers are staggering. About 5000 or so ideas thought worthy of beginning the testing that starts with non human toxicity studies turns into just a handful thought suitable for phased human toxicity studies and trials per year. It costs around one-half to up to a billion dollars to develop a major new drug and typically 3-5 years. Patents are not lifelong and generic drugs do follow after reasonable times.
For those in the know, the FDA does more (and by extension the USA) of drug development and testing with amazing track records of accuracy than any other nation or consortium. Drug companies or big pharmacies are neither robber barons nor angels. Their profit margin, what they actually return after all costs, is not spectacular and they can go years working on reserves before the next great drug comes along. There has been no better system shown for providing mankind with safe and effective oncology medicines.
Some cancers treatments require the death or disabling of all cancer cells in the patient capable of dividing and growing and or spreading. Some treatment may not remove all viable cancer cells but remove the ability of those cells to repeat the havoc of what preceded treatment. As a result, patients are living longer and often with a better quality of life. In some types of cancer, it is becoming more of a chronic disease that must be managed and controlled over the course of many years and maintained until new discoveries in treatment are made.
For the last several decades, the common cancer treatment methods have been surgery, radiation, and chemotherapy. While these treatments are focused on destroying the tumor cells, they can damage normal cells in the process or may have significant treatment related toxicity.
The newest category of cancer treatments are targeted therapies that act in specialized ways to destroy or act against tumor cells, often not affecting normal cells. These are innovative therapies, many of which were scoffed at less than a couple decades ago but are now commercially available with bold new trials launching nearly weekly internationally. These therapies are based on discerning something unique about the cancer cell or some sort of potential Achilles heel that can be exploited while not harming normal tissue. As a result, patients may experience less severe side effects. The newer treatments can also be combined with older therapies to enhance anti-tumor effectiveness.
The bottom line is that although all therapy is not individualized and may never completely be, the distance from laboratory bench to patients’ bedside is shrinking. Soon therapies will exploit singular or multiple areas of tumor vulnerability at the molecular and even genetic level, all as a result of fundamental research your tax dollars (in large part) support. Soon therapies will be more patient specific.
Because of improved early detection and better cancer treatments, there are approximately 9.6 million cancer survivors alive today in the United States. This compares with only 3 million people with a history of cancer who were alive in 1971.
Another potent message is the marriage of technologies. As discussed a number of times, we are often marrying the anitigenicity or chemical reactivity or genetic fingerprinting of tumor cells with CAT scans and MRI. This is done to detect and then “see” both the primary tumor but hopefully early depots of spread and in the case of the marrow, presence even on the single cell level. The notion of intellectual partnership in medicine is crucial. In Oncology, our tools function best when in synergy ( where for example one plus one equals three); Critical thinking and well constructed trials based on good science casts a long shadow